On 5 April 2024, the US Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options.
Efficacy was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumours who were enrolled in one of three multicentre trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). All three trials excluded patients with a history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status >1. Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.
The major efficacy outcome measure in all three trials was confirmed objective response rate (ORR), and an additional efficacy outcome was duration of response (DoR). All outcomes were assessed by independent central review (ICR) based on RECIST v1.1. In DESTINY-PanTumor02, ORR was 51.4% (95% confidence interval [CI] 41.7, 61.0) and median DoR was 19.4 months (range 1.3, 27.9+). In DESTINY-Lung01, ORR was 52.9% (95% CI 27.8, 77.0) and median DoR was 6.9 months (range 4.0, 11.7+). In DESTINY-CRC02, ORR was 46.9% (95% CI 34.3, 59.8), and DoR was 5.5 months (range 1.3+, 9.7+).
The most common adverse reactions (≥20%), including laboratory abnormalities, were decreased white blood cell count, nausea, decreased haemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhoea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection. The prescribing information includes a Boxed Warning advising health professionals of the risk of interstitial lung disease and embryo-foetal toxicity.
The recommended fam-trastuzumab deruxtecan-nxki dosage for this indication is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
This tumour agnostic indication is approved under accelerated approval based on ORR and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Singapore’s Health Sciences Authority. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application almost 2 months ahead of the FDA goal date.
This application was granted Priority Review and Breakthrough Therapy Designation.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate.